Basic amides of bicyclo [2. 2.1]-5-heptene-2-carboxylic acid and 2-norcamphanecarboxylic acid and derivatives thereof



Patented June 22, 1954 UNITED STATES PATENT OFFICE BASIC AMIDES OFBICYCLO [2.2.11--HEP- TENE-Z-CARBOXYLIC ACID AND Z-NOR-CAM?I-IANECARBOXYLIC ACID AND DE- RIVATIVES THEREOF William W. Jenkins,Wilmette, Ill., assignor to G. D. Searle & 00., Chicago, Ill., acorporation of Illinois No Drawing. Application December 7, 1951, SerialNo. 260,575

11 Claims.

and salts thereof, wherein A is either an ethylene or a vinylene group,B is a lower bivalent aliphatic hydrocarbon radical containing at least2 carbon atoms, X and Y are either hydrogen or lower alkyl radicals, Zis either a hydrogen, lower alkyl, or phenyl radical, and NRR' is eithera lower dialkylamino group or a nitrogen containing heterocyclic groupattached to the radical B through a nitrogen in the heterocycle.

In the foregoing structural formula the radical B is derived from suchstraight-chained, or branch-chained aliphatic hydrocarbon radicals asethylene, propylene, butylene, amylene, and hexylene, or a polymethyleneradical such as trimethylene, tetramethylene, pentamethylene, andhexamethylene. The radicals R and R can be lower alkyl groups such asmethyl, ethyl, and straight-chained and branch-chained propyl, butyl,amyl, and hexyl groups. The radical NRR can also be 9.nitrogen-containing lower heterocycle such as a morpholino, pyrrolidino,piperidino, 2,5-dimethylpyrrolidino, 2,6-lupetidino, piperazino,N'-alkylpiperazino, thiamorpholino, quinolino, and isoquinolino radical.

The radicals X, Y, and Z can be hydrogen or lower alkyl radicals and, inaddition, Z can be a lower aryl radical.

The organic bases described herein form salts with a variety ofinorganic and strong organic acids, including sulfuric, phosphoric,hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic,malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, oxalic,ascorbic, and related acids. They also form quaternary isoquinoliniumsalts with a variety of organic esters of sulfuric, hydrohalic, andaromatic sulfonic acids. Among such esters are methyl chloride, bromideand iodide; ethyl chloride, propyl chloride, butyl chloride, isobutylchloride, benzyl 2 chloride, phenethyl chloride, naphthylmethylchloride, dimethyl sulfate, methyl benzenesulfonate, ethyltoluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allylbromide, methallyl bromide, and crotyl bromide.

The bicyclo [2.2.1] -5-heptene 2 carboxylic acids and their alkylationand their 2- and 3- substitution products (in which A is vinylene) areprepared by a Diels-Alder addition of a compound of the type Y z \C/Xll/ coo-D wherein D is hydrogen or a lower alkyl group and the othersymbols are defined as hereinabove, to cyclopentadiene as described byAlder et al., Annalen der Chemie, vol. 514, pages 197 et seq., 1934; andby Fiesselmann, Berichte deut. chem. Ges., vol. '75, pages 881 et seq.,1942. The acids are then converted into the acid halides and the latterreacted with a compound of the type.

to form the desired amides.

The derivatives of 2-norcamphanecarboxylic acid are obtained byhydrogenating the bicyclo- [2.2.1]-5-heptene-2-carboxylic acids in thepresence of a catalyst such as Raney nickel or palladium, conversion ofthe resulting acids to the acid halides and the reaction with a suitableamine.

The amides which constitute the subject of the present invention arevaluable intermediates in organic synthesis. The addition salts are ofspecial interest as medicinal agents because of their effects on thecardio-vascular and renal systems. The quaternary ammonium salts are ofspecial value because of their inhibitory effect on the autonomicnervous systems.

My invention will appear in further detail from the following exampleswhich are set forth for the purpose of illustrating the invention butare in no way to be construed as limiting it. in spirit or in scope. Itwill be apparent to those skilled in the art that many modifications inmaterials, methods, and conditions can be adopted without departing fromthe scope of this invention. In these examples temperatures are givenuncorrected in degrees Centigrade C.) pressures during vacuumdistillation in millimeters (min) of mercury, and quantities ofmaterials in parts by Weight.

EXAMPLE 1 N- (fi-diethylaminoethyl) bicylcl[ 2.2.1]heptene-Z-carboxamide A mixture of 250 parts of bicyclo[2.2.1l-5-heptene-2-carboxylic acid, 220 parts of thionyl chloride, and 150 partsof pyridine in 1300 parts of benzene is heated at. reflux temperaturefor 90 minutes, cooled and filtered. To the filtrate, containing asolution of the bicyclo[2.2.1]-5-heptene-2-carboxylic acid chloride, 210parts of B-aminoethyl-diethylamine are added and the mixture is heatedat reflux temperature for 5 hours, after which the solvent is strippedand the residue is extracted with water. The aqueous solution is washedwith. ether, rendered alkaline by the addition of sodium hydroxide andextracted with ether. The ether extract is dried over anhydrouspotassium carbonate, filtered and evaporated. Distillation of theresidue at about 139-141 C. and 0.8-1.0 mm. pressure yields theN-(fi-diethylaminoethyl)-bi cyclo [2.2.1] -5-heptene-Z-carboxamide.

224 parts of the base thus obtained are dissolved in 3000 parts ofanhydrous ether and treated with one equivalent of a 25% solution ofhydrogen chloride in absolute alcohol. Upon chilling the whitehydrochloride precipitates which is very hygroscopic. It has thestructural formula firol EXAMPLE 2 N ,8-diethylaminoethyl)-2-norcamphanecai'boxamide A solution of 150 parts of2-norcamphanecarboxylic acid, 131 parts of thionyl chloride, 86 parts ofpyridine, and 900 parts of benzene is heated at reflux temperature for9.0 minutes, cooled and filtered. To the filtrate, containing the2-norcamphanecarboxylic acid chloride, 124 parts ofp-aminoethyldiethylamine are added and the solution is heated at refluxtemperature for 6 hours. After concentration in vacuum the residue isextracted with water and the extract is washed with ether, renderedalkaline by addition of potassium hydroxide and extracted with ether.This ether extract is dried over anhydrous calcium sulfate, filtered andevaporated. The N (,8 diethylaminoethyl) 2 norcamphanecarboxamide thusobtained is distilled at about 132--134 C. and 0.5 mm. pressure.

A solution of this base in absolute ether is treated with a 25% solutionof hydrogen chloride in anhydrous 2-propanol. The hygroscopichydrochloride melts at about 90-94 C. It has the structural formulaEXAMPLE 3 N c-dz'ethylaminoethyl) -2-m ethyl-bicycl o [2.2.1]-5-heptene-2-.c arboacamide A mixture of 300 parts of 2-methyl-bioyclo-[2.2.1]-5-heptene-2-carboxylic acid, 235 parts of thionyl chloride, 156parts of pyridine, and 900 parts of benzene is heated at refluxtemperature for minutes, cooled and filtered. To the liltrate,containing the 2-methyl-bicyc1o[2.2.ll-5- heptene-Z-carboxylic acidchloride, 236 parts of 3aminoethyldiethylamine are added cautiously andthe solution is heated at reflux temperature for 6 hours. The solvent isstripped oil. and the residue extracted with water. The aqueous solutionis washed with ether, rendered alkaline by addition of ammoniumhydroxide, and extracted with ether. This ether extract is dried overanhydrous potassium carbonate, filtered and evaporated, leaving an oilyresidue which is distilled at about 128130 C. and 0.4-0.5 mm. pressure.

415 parts of the N-(B-diethylaminoethyl)-2- methyl bicyclo[2.2.l] 5heptene 2 carboxamide are dissolved in 6000 parts of anhydrous ether andtreated with one equivalent of an a solute alcoholic solution ofhydrogen chloride. The resulting oil solidifies on chilling. Uponrccrystallization from anhydrous ethyl acetate the somewhat hygroscopic,white hydrochloride melts at about 119-119.5 C. The salt has thestructural formula EXAMPLE 4 N (,B-dz'ethylaminoethyl) -2-methyZ-2-norcamphanecarboacamide A mixture of 180 parts of 2-methyl-2-norcamphanecarboxylic acid, 139 parts of thionyl chloride, 93 parts ofpyridine, and 900 parts of benzene is heated at reflux temperature for 2hours, cooled and filtered. To the filtrate, containing the2-methyl-2-norcamphanecarboxylic acid chloride, 136 parts ofB-aminoethyldiethylamine are added and the resulting solution is heatedat reflux temperature for 5 hours, after which the solvent is strippedoil and the residue is extracted with water. The aqueous solution iswashed with ether, rendered alkaline by addition of sodium hydroxide andextracted with ether. The ether extract is dried over anhydrouspotassium carbonate, filtered and evaporated to yield theN-(B-diethylaminoethyl)-2-methyl-2- norcamphanecarboxamide which isdistilled at about 144-146" C. and 1.4 mm. pressure. It has thestructural formula EXAMPLE 5 N- (/3-diethylaminoethyl) -3-methyl-bicyclo[2.2.1] -S-heptene-Z-carboxamide A mixture of 250 parts ofB-methyl-bicyclo [2.2.1]-5-heptene-2-carboxylic acid, 196 parts ofthionyl chloride, parts of pyridine and 900 parts of benzene is heatedat reflux temperature for 90 minutes, cooled and filtered. To theilltrate, containing the 3-methyl-bicyclo[2.2.1]-

- ether.

5-heptene-2-carboxylic acid chloride, are added 191 parts offi-aminoethyldiethylamine and the resulting solution is heated at refluxtemperature for 5 hours, after which the solvent is stripped off and theresidue is extracted with water. After washing with ether, the aqueoussolution is rendered alkaline by addition of sodium hydroxide andextracted with ether. The ether extract dried over anhydrous potassiumcarbonate, filtered and evaporated to yield the N (c diethylaminoethyl)3 methyl-bicyclo- [2.2.1]-5-heptene-2-carboxamide which is distilled atabout 142-1 C. and 1.1 mm. pressure.

An absolute ether solution of this base is treated with one equivalentof a solution of hydrogen chloride in absolute 2-propanol, and theresulting white precipitate is recrystallized from absolute ethylacetate. The hydrochloride which melts at about 99-100 C. has thestructural N B-diethylaminoethyl) -3methyl-2- norcamphanecarbowamide Amixture or" 150 parts of 3-methyl-2-norcamphanecarboxylic acid, 116parts of thionyl chloride, '77 parts of pyridine, and 900 parts ofbenzene is heated at reflux temperature for 100 minutes, cooled andfiltered. To the filtrate, containing a solution of the3-methyl-2-norcamphanecarboxylic acid chloride, are added 113 parts offi-aminoethyldiethylamine and the resulting solution is heated at refiuxtemperature for 5.5 hours, after which it is concentrated and extractedwith water. The aqueous extract is washed with ether, rendered alkalineby addition of sodium hydroxide, and extracted with This ether extractis dried over anhydrous calcium sulfate, filtered and evaporated toyield the N-(fi-diethylaminoethyl) -3-methyl- Z-norcamphanecarboxamidewhich is distilled at about 1 17-150" C. and 1.2 mm. pressure.

To a solution of 201 parts of this base in 3000 parts of absolute etheris added one equivalent of a 25% solution of hydrogen chloride inanhydrous 2-pr0panol. The white precipitate is washed with ether, dried,and recrystallized from anhydrous ethyl acetate. The hydrochloride meltsat about 82-85" C. and has the structural formula EXAMPLE 7 N(a-dimethylaminobutyl) -2,3-dz'eth' Z2- norcamphenecarboramide A mixtureof 100 parts of 2,3-diethyl-2-norcamphenecarboxamide, 61 parts ofthionyl chloride, 11 parts of pyridine, and 400 parts of benzene isheated at reflux temperature for 2 hours, cooled and filtered. To thefiltrate, containing the 2,3- diethyl-Z-norcamphenecarboxylic acidchloride, are added 60 parts of 6-aminobutyldimethylamine and thesolution is heated at reflux temperature for 7 hours. The solvent isstripped off in vacuum and the residue taken up in water. The aqueoussolution is washed with ether, rendered alkaline by addition ofpotassium hydroxide and extracted with ether. This ether extract isdried over anhydrous calcium sulfate, stirred with decolorizingcharcoal, filtered and evaporated. The N-(t-dimethylaminobutyl) 2,3diethy 2 norcamphanecarboxamide is distilled at about 152-1525 0. andabout 0.4 mm. pressure. The yellowish oil has the structural formulaEXAMPLE- 8 N diisopropylaminogcropyl)-3,3-dimethylbicyclo[2.2.1l-5heptene2-carboxa-mide A mixture of 332parts of 3,3-dimethyl-bicyclo- [2.2.1]-5heptene-2-carboxamide, 240 partsof thionyl chloride, 158 parts of pyridine, and 1500 parts of benzene isheated at reflux temperature for 2 hours, cooled and filtered. To thefiltrate, containing the 3,3 dimethylbicyc1o[2.2.ll 5-heptene-Z-carboxylic acid chloride, are added 316 parts of'yaminopropyldiisopropylamine and the mixture is heated at refluxtemperature for 10 hours, concentrated in vacuum, and extracted withether. After washing with ether, the aqueous solution is renderedalkaline by addition of sodium hydroxide and extracted with ether. Theether extract is dried over anhydrous potassium carbonate, stirred withdecolorizing charcoal, filtered and evaporated to leave the oily N ('ydiisopropylamino proply) 3,3 dimethyl bicyclo[2.2.1l5-heptene-2-carboxamide which is distilled at about 157-161 C. and 0.4-0.6 mm. pressure. The clear, yellowish oil has the structural formula:

EXAMPLE 9 A mixture of 640 parts of 3-phenyl-bicyclo-[2.2.1]-5-heptene-2-carboxylic acid, 356 parts of thionyl chloride, 2 10parts of pyridine, and 3000 parts of toluene is heated at refluxtemperature for 2 hours, cooled and filtered. The filtrate, containingthe 3-phenyl-bicyclo- 2.2.1] -5heptene- 2-carboxylic acid chloride, istreated with 560 parts of 'y-aminopropyldibutylamine and heated atreflux temperature for 9 hours. After concentration in vacuum theresidue is extracted with water and the aqueous extract is washed withether, rendered alkaline by addition of sodium hydroxide, and extractedwith ether. This ether extract is dried over anhydrous calcium sulfate,stirred with decolorizing charcoal, filtered and evaporated to yield theN-(v-di-n-butylaminopropyl) 3 phenyl bicyclo [2.2.1] 5-heptene-Z-carboxamide as a clear, amber oil which has the structuralformula wherein A is a member of the class consisting of ethylene andvinylene, B is a lower alkylene radical separating the two nitrogenatoms by at least two carbon atoms, X is a member of the classconsisting of hydrogen and lower alkyl radicals and Y is a member of theclass consisting of the methylene radical, Cl-I(lower alkyl) radicalsand, in the case where X is a hydrogen radical, C(lower alkyDzand--CH(phenyl)- radicals.

2. A di-(lower) alkylamino- (lower) alkylbicyclo[2.2.1]-5-heptene-2-carboxamide, wherein the two nitrogen atoms are separatedby at least two carbon atoms.

3. A lower N-dialkylaminoalkyl-2-(lower) alkyl-bicyclo[ 2.2.1]-5-heptene-2-carboxamide of the structural fiormula (JO-NH-B-NRR whereinB is a lower alkylene radical separating the two nitrogen atoms by atleast two carbon atoms, and R, R, and X are lower alkyl radicals.

4. A lower N dialkylaminoalkyl 3 (lower) alkyl-bicyclo[ 2.2.1]-5-heptene-2-carboxamide of the structural formula wherein B- is a loweralkylene radical separating the two nitrogen atoms by at least twocarbon atoms, and R, R, and Y are lower alkyl radicals.

5. A di- (lower) alkylamino- (lower) alkyl-2-norcamphenecarboxamide,wherein the two nitrogen atoms are separated by at least two carbonatoms.

6. A lower N-dialkylaminoalkyl-3-(lower) alkyl-2-norcamphanecarboxamideof the structural formula C I o References Cited in the file of thispatent UNITED STATES PATENTS Name Date Graenacher et al Jan. 4, 1944Number

1. AN AMIDE OF THE STRUCTURAL FORMULA